Partial chromosome 21 monosomy is sometimes associated with severe clinical phenotypes, such as brain dysgenesis, extensive dysmorphic features, and heart defects.5, 6, 7, 8, 9
However, other patients present with very few dysmorphic features or congenital anomalies.10, 11
It is important to understand the genotype–phenotype correlation to elucidate the consequence of particular hemizygous deletions. In the present study we have characterized ten 21q monosomy cases, as well as described 12 cases from the DECIPHER database. We characterized the deletion breakpoint regions using high-density SNP arrays, and we provide descriptions of clinical phenotypes of varying severity.
We interpret the significance of our findings in the context of a model recently presented by Lyle et al2
and we extend that model. They reported 11 partial monosomy 21 cases (summarized in ) as well as cases of partial trisomy 21, and they described three broad classes of partial 21 monosomy (). In the first region, deletions from the centromere to ~31.2
Mb (spanning about 50 genes) are associated with a severe phenotype. In our study this region included Cohort A Patient 3, three Cohort B cases, and two DECIPHER cases (). Consistent with Lyle et al
deletions in this region tended to be large (three extended over 15 Mb). Although Patient 3 had a deletion encompassing approximately half of the q-arm of chromosome 21, she had few dysmorphic features and no detectable congenital brain, heart or kidney abnormalities. We note that two of the four cases in region 1 from Lyle et al2
as well as two of our cases had deletions or translocations involving chromosomes other than 21, and this may contribute to the clinical severity. Lindstrand et al9
reported three partial 21q deletion cases. Their patient 1, who died at the age of 5 months, had a complex intrachromosomal rearrangement involving four duplicated and four deleted segments, including a large deletion in Region 1. Their patient 3 had a 14
Mb hemizygous deletion in Region 1. This child had normal to late speech development, some problems in gross and fine motor functions, and normal to mildly delayed social, emotional, and cognitive development.
In the second region, from 31.2 to 36
Mb, Lyle et al2
found no cases that spanned the interval and only one case had a partial deletion. They suggested that deletions of this region, harboring ~80 genes, produce a severe phenotype not compatible with survival. We report one Cohort A and three Cohort B cases having deletions overlapping Region 2. Lindstrand et al9
reported Patient 2 () having an 11.9 Mb hemizygous deletion that spanned part of Region 1 and half of Region 2, with severely delayed psychomotor function and some dysmorphic features. Three DECIPHER cases occur in this region, two of which almost span it. This suggests that region 2 could be merged with Region 1. The severity of clinical presentation for deletions spanning this region was variable, and appears comparable with that of Region 1.
In agreement with Lyle et al
we also found hemizygous deletions in a third region, from ~36–37.5
Mb to the telomere, to be the most common abnormality (two from Cohort A, four from Cohort B, eight from DECIPHER, seven from Lyle et al
). Also in agreement with Lyle et al
, the phenotypes were relatively mild. Although deletions in this region were common, the breakpoint locations were variable.
We depict the chromosome 21q deletion breakpoints for 36 cases in . Of these, 16 cases involve no other identified chromosomal abnormalities, whereas 20 cases involve aneuploidy and/or a translocation on a chromosome other than 21. We may reasonably exclude these latter cases from the analysis of genotype/phenotype correlations because the effects of additional chromosomal abnormalities are too complex to interpret. Our interpretation of the 16 cases as a group still suggests that Regions 1 and 2 may be combined. There is still considerable variability in the severity of the phenotype considering this larger region. This interpretation is consistent with that of Lindstrand et al9
who reviewed 35 published cases of 21q deletion. They proposed that a small region (from 33.83 to 33.99 Mb), including the ITSN1
gene, is deleted in most patients with mental retardation or severe developmental delay; and further they suggested that the neighboring genes KCNE1
form a critical region of severe cardiac malformations. This region was not affected in cases from Cohort A or B, and although case 42 from Lyle et al
does include this region (), that patient also has a X chromosome aneuploidy that could impact the cardiac phenotype. This highlights the current challenge of identifying genes responsible for developmental abnormalities in partial 21q deletion cases.
We conclude that the variability of clinical phenotypes reflect the variable sizes of the hemizygous deletion, the location of the deletion, the influence of variants at other chromosomal loci in each individual's genome, and other environmental factors. As we continue to determine breakpoint locations and standardize the way clinical phenotype data are collected, we may further discern candidate loci for particular phenotypes associated with these deletions.